EXTH-70. UTILIZING ONCOLYTIC VIROTHERAPY AS AN APPROACH TO ENHANCE NEOANTIGEN SPECIFIC IMMUNE RESPONSES IN GLIOBLASTOMA

Abstract

Abstract Despite the success in treating many solid cancers, immunotherapy has not shown significant efficacy in patients with glioblastoma (GBM). The lack of tumor-infiltrating T cells recognizing tumor antigens displayed with major histocompability complex I (MHC I) is one of the reasons for GBM’s evasion from immunotherapy. Our preclinical GBM models and an ongoing clinical trial with oncolytic herpes simplex virus-1 (oHSV) at our institution (NCT03152318) demonstrated that oHSV treatment leads to an increase influx of CD8+ and CD4+ T cells into tumor. However, it remained unclear whether these T cells are specific to the tumor antigens (neoantigens) or reactive to only viral antigens. To determine whether infiltrating CD8 T cells target tumor antigens, we first performed whole-exome and RNA sequencing of CT2A, a preclinical model of GBM impervious to immunotherapies for identification of neoantigens. We screened immunogenicity of identified neoantigens by ELISPOT assay. TILs from the oHSV-treated (but not from control group) reacted to two of the neoantigens that were identified with our pipeline and this activation was similar in magnitude to the reaction to the immunodominant HSV antigen. FACS analyses of TILs seven days after virotherapy showed that oHSV-treated tumor had higher level of TILs than vehicle control tumors, a finding that mirrored what we observed in our phase 1 clinical trial with oHSV. High dose of oHSV treatment not just induces the infiltration of viral specific T cells, but infiltration of T cells targeting neoantigens that were not presented without OV infection. Phosphoproteomic analysis of bulk tumor revealed activation of key inflammatory pathways, including that of T cells receptor signaling upon virus treatment. We evaluated the efficacy of therapeutic neoantigen vaccination in combination with oncolytic intratumoral virotherapy. Survival analysis showed that combination therapy not just delays the tumor progression but also provides survival advantage compared to monotherapies.